Zoledronic acid is known as (1-hydroxy-2-imidazol-1-yl-1-phosphono-ethyl)phosphonic acid. Zoledronic acid is depicted by the following chemical structure:
Zoledronic acid is a third generation bisphosphonate which far exceeds the previous generations in terms of efficacy and is used predominately for indications of osteoporosis or tumor induced hypercalcemia (TIH). It was originally developed by Novartis and marketed in a monohydrate form under the Zometa® and Reclast® brand names. Zoledronic acid was first approved in 2000 for the treatment of TIH in Canada. It was later approved for use in the US in 2001 for indications of TIH and in 2007 for osteoporosis and Paget's disease. Clinical trials have also been conducted or are on-going exploring the use of zoledronic acid in neoadjuvant or adjuvant cancer therapy, Coleman, et al., British J Cancer 2010; 102(7):1099-1105, Gnant, et al., New England J Medicine. 2009, 360 (17):679-691 and Davies, et al. J Clinical Oncology, 2010, 28(7s): Abstract 8021. Zoledronic acid is administered as an intravenous (IV) dose of 4 mg over 15 minutes for TIH and 5 mg over 15 minutes for osteoporosis.
Zoledronic acid is sparingly soluble in water and 0.1 N HCl solution but is freely soluble in 0.1 N NaOH. Zoledronic acid is practically insoluble in many organic solvents.
Various efforts have been taken to generate novel oral formulations of zoledronic acid through crystallization and metal salt formation to improve its aqueous solubility, permeability, and subsequent oral bioavailability. A crystalline trihydrate was disclosed in U.S. Patent application 2006/0178439 A1 and world patent application WO2007/032808. Seven hydrated forms, an amorphous form, three monosodium salts, and eleven disodium salts with varying degrees of hydration of zoledronic acid were also disclosed in the world patent application WO2005/005447 A2. Zoledronate metal salts including Na+, Mg2+, Zn2+ were reported in the monthly issued journal Drugs of the Future (Sorbera et al, 25(3), Drugs of the Future, (2000)). Zoledronate, zoledronic, or zoledronic salt represents the ionic form of zoledronic acid. A recently filed patent application (WO2008/064849 A1) from Novartis disclosed additional metal salts including two Ca2+ salts, two Zn2+ salts, one Mg2+ salt, as well as a mono and trihydrate, an amorphous form, and an anhydrous form.
The low oral bioavailability of zoledronic acid, which is <1% of the oral dose, can be attributed to poor permeability in the gastrointestinal (GI) tract. It was also noted that insoluble metal complexes were formed in the upper intestines, most commonly with calcium. Zoledronic acid has also been shown to cause severe GI irritation both in the stomach and in the intestines. In some cases the irritation was so severe that medical treatment was required. Recent activity concerning the development of oral formulations has led to the use of medium chain fatty acids to enhance the drug's low permeability as disclosed in the US 2007/0134319 A1 and US 2007/0196464 patent applications. Modified amino acid carriers, but not pure proteinogenic amino acids, have also been employed to improve the absorption of the drug as shown in the WO 2007/093226 A1 application.
In general, sparingly water soluble, provides substantial challenges for drug development of parenteral formulations due to the amount of solvent needed to dissolve the drug which could render it more suitable for infusion. Typically, the greater the volume needed to be administered parenterally to a patient, the longer the infusion time, the higher the likelihood of a vehicle-related adverse effect, the more expensive the product, and the less likelihood that the formulation will be found acceptable by the patient. By improving the aqueous solubility of the drug the volume of solvent needed for reconstitution can therefore be dramatically reduced rendering it suitable for injection rather than infusion.
Due to the fact that zoledronic acid is only available as a parenteral dosage form (infusion over at least 15 minutes) there is a clear need to develop novel forms of zoledronic acid that can be included in an oral dosage form particularly as the use of orally administered drugs are becoming more wide spread in many therapeutic areas including the treatment of cancer. The upward trend in the use of oral drugs will continue especially in light of the goal to decrease the overall cost of healthcare. Thus, there is an opportunity to create oral dosage forms of IV drugs only where oral dosage forms do not yet exist due to their poor aqueous solubility and/or poor permeability providing a clear clinical benefit for patients. In addition, opportunity is also provided to improve the solubility of sparingly water soluble drugs by creating molecular complexes of such drugs with standard (proteinogenic) amino acids that can subsequently be incorporated in dosage forms for a variety of drug delivery systems.
The development of oral forms of zoledronic acid to enhance the aqueous solubility or permeability has thus far been problematic. However, by using the novel approach of generating molecular complexes of zoledronic acid with standard amino acids there is an opportunity provided to improve the solubility and/or permeability resulting in a new dosage form suitable administration to humans.